The expression of VGF, a secreted polypeptide that is synthesized by neurons and neuroendocrine cells, is induced rapidly by neurotrophins in vitro and is regulated by electrical activity, injury and the circadian clock in vivo. Although found throughout the adult brain, VGF is particularly abundant in the hypothalamus. To gain insight into the function of VGF in vivo, the applicant has generated mice with a null mutation of the Vgf gene. Mice lacking VGF are indistinguishable at birth from normal littermates, but gain weight very slowly prior to weaning and remain 50-70 percent the size of normal or heterozygous littermates throughout adult life. Ad lib fed adult homozygous mutant mice are hyper metabolic, hyperactive, and relatively infertile with markedly reduced peripheral fat stores. Altered hypothalamic POMC, NPY, and AGRP expression and low peripheral leptin levels suggest that ad lib fed VGF mutant mice have the neuroendocrine profile of a fasted animal. Furthermore, in situ hybridization studies demonstrate induction of VGF mRNA in the hypothalamic arcuate nucleus of fasted normal mice. VGF therefore plays a critical role in the regulation of energy homeostasis, suggesting that study of lean VGF mutant mice may provide insight into wasting disorders and obesity. This proposal seeks support to identify the neuroanatomic distribution of VGF in the hypothalamus (Aim 1), functional mechanisms responsible for resistance to obesity in VGF mutant mice (Aim 2), and mechanisms of regulation of VGF in the hypothalamus (Aim 3). The applicant further propose to determine the results of over expression of VGF in transgenic models and to examine the ability of these mice to rescue the phenotype of VGF mutant mice in genetic cross experiments (Aim 4), to elucidate the contribution of the autonomic nervous system and brown adipose tissue to cachexia and the phenotype of VGF mutant mice (Aim 5), and to examine the role that VGF plays in processing and regulated release of co-expressed neurotransmitters (Aim 6).